ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
NXP800 Activates the Unfolded Protein Response, Altering AR and E2F Function to Impact Castration-Resistant Prostate Cancer Growth.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- The Novel HSF1 Inhibitor NXP800 Exhibits Robust Antitumor Activity in Hepatocellular Carcinoma.International journal of molecular sciences · 2026Article
- Heat shock transcription factors in development and disease.Disease models & mechanisms · 2026Review
- Activating GCN2 and subsequently the Unfolded Protein Response with the small oral molecule NXP800 delays tumor growth in osteosarcoma.Cell death discovery · 2026Article
- A PHF19-YTHDC1 condensate switches EZH2-mediated gene suppression to activation for prostate cancer progression.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- HSF1-DBC1 axis drives prostate cancer progression by activating a metastatic transcriptional program.Experimental & molecular medicine · 2025Article
- Review
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Authors and funding
40 authors.
Funding
Abstract
purposeAdvanced prostate cancer is invariably fatal, with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced prostate cancer, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is to target heat shock proteins (HSP) critical to AR functional activity. EXPERIMENTAL
designWe first did transcriptome analysis on multiple castration-resistant prostate cancer (CRPC) cohorts to correlate the association between the Gene Ontology cellular response to heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely, NXP800 (formerly CCT361814), in models of treatment-resistant prostate cancer. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant model and an in vivo model of CRPC.
resultsWe report that in multiple CRPC transcriptome cohorts, the Gene Ontology cellular response to heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely, NXP800, in prostate cancer. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant prostate cancer models.
conclusionsOverall, NXP800 has antitumor activity against treatment-resistant prostate cancer models, including molecular subtypes with limited treatment options, supporting its consideration for prostate cancer-specific clinical development.
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